Polygenic predisposition to venous thromboembolism is associated with increased COVID-19 positive testing rates

Genetic predisposition to venous thrombosis may impact COVID-19 infection and its sequelae. Participants in the ongoing prospective cohort study, Million Veteran Program (MVP), who were tested for COVID-19, with European ancestry, were evaluated for associations with polygenic venous thromboembolic risk, Factor V Leiden mutation (FVL) (rs6025) and prothrombin gene 3 -UTR mutation (F2 G20210A)(rs1799963), and their interactions. Logistic regression models assessed genetic associations with VTE diagnosis, COVID-19 (positive) testing rates and outcome severity (modified WHO criteria), and post-test conditions, adjusting for outpatient anticoagulation medication usage, age, sex, and genetic principal components. 108,437 out of 464,961 European American MVP participants were tested for COVID-19 with 9786 (9%) positive. PRS(VTE), FVL, F2 G20210A were not significantly associated with the propensity of being tested for COVID-19. PRS(VTE) was significantly associated with a positive COVID-19 test in F5 wild type (WT) individuals (OR 1.05; 95% CI [1.02-1.07]), but not in FVL carriers (0.97, [0.91-1.94]). There was no association with severe outcome for FVL, F2 G20210A or PRS(VTE). Outpatient anticoagulation usage in the two years prior to testing was associated with worse clinical outcomes. PRS(VTE) was associated with prevalent VTE diagnosis among both FVL carriers or F5 wild type individuals as well as incident VTE in the two years prior to testing. Increased genetic propensity for VTE in the MVP was associated with increased COVID-19 positive testing rates, suggesting a role of coagulation in the initial steps of COVID-19 infection. Key PointsO_LIIncreased genetic predisposition to venous thrombosis is associated with increased COVID-19 positive testing rates. C_LIO_LIPRS for VTE further risk stratifies factor V Leiden carriers regarding their VTE risk. C_LI

A MUC5B gene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection

RationaleA common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear. ObjectivesTo assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI). MethodsMVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of a MUC5B rs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2, and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions. Measurements and Main ResultsA COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 x 10-5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 x 10-6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement. ConclusionsThe MUC5B variant rs35705950-T is protective in COVID-19 infection.

IL10RB as a key regulator of COVID-19 host susceptibility and severity

BackgroundRecent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step. MethodsWe integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by in vitro perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the in silico drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence. ResultsWe identify IL10RB as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. In vitro IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19. ConclusionsWe establish an integrative data-driven approach for gene target prioritization. We identify and validate IL10RB as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.

Efficacy of Xiaoer Jinqiao granule combined with interferon α-2b on acute herpangina in children and its effect on immune function and myocardial enzyme level / 中国基层医药

Objective:To investigate the efficacy of Xiaoer Jinqiao granule combined with interferon α-2b on acute herpangina in children and its effect on immune function and myocardial enzyme. Methods:A total of 102 children with acute herpangina who received treatment in Hangzhou Ninth People's Hospital from January 2019 to January 2020 were randomly assigned to receive treatment with either interferon α-2b (control group, n = 51) or Xiaoer Jinqiao granule combined with interferon α-2b (observation group, n = 51) for 5 d. The time to disappearance of main symptoms, changes in humoral immune function, changes in cellular immune function and myocardial enzyme level after treatment relative to before treatment as well as curative effect were compared between the control and observation groups. Results:The time to disappearance of pharyngeal herpes [(3.05 ± 0.74) d], salivation [(2.31 ± 0.68) d], and fever [(1.36 ± 0.39) d] in the observation group were significantly shorter than those in the control group [(4.38 ± 0.98) d, (3.83 ± 1.07) d, (2.54 ± 0.71) d, t = 7.773, 8.562, 10.403, all P < 0.05]. After treatment, serum IgA [(1.49 ± 0.16) g/L], IgG [(10.29 ± 0.89) g/L] and IgM [(1.26 ± 0.14) g/L] levels in the observation group were significantly higher than those in the control group [(1.13 ± 0.12) g/L, (9.35 ± 0.72) g/L and (0.98 ± 0.13) g/L, t = 12.855, 5.864 and 10.466, all P < 0.05]. After treatment, CD 3+ [(74.29 ± 2.15)%], CD 4+ [(40.85 ± 1.65)%] and CD 4+/CD 8+ expression [(1.87 ± 0.23)] in the observation group were significantly higher than those in the control group [(67.96 ± 2.43)%, (38.02 ± 1.20)% and (1.49 ± 0.14), t = 13.933, 9.906 and 10.079, all P < 0.05]. After treatment, serum creatine kinase [(147.86 ± 15.42) U/L] and lactate dehydrogenase [(128.64 ± 14.25) U/L] in the observation group were significantly lower than those in the control group [(176.95 ± 13.15) U/L and (184.32 ± 18.98) U/L, t = 10.251, 16.754, both P < 0.05]. Total effective rate in the observation group was significantly higher than that in the control group [92.16% (47/51) vs. 74.51% (38/51), χ 2 = 5.718, P < 0.05]. Conclusion:Xiaoer Jinqiao granule combined with interferon α-2b has obvious curative effect on acute herpangina in children because it can improve the humoral and cellular immune function and reduce myocardial damage.

Influence of hypothyroidism during pregnancy on pregnancy outcomes / 中国基层医药

Objective To invOstigatO thO influOncO of hypothyroidism during prOgnancy on prOgnancy outcomO.Methods From January 2016 to January 2018, 1 000 prOnatal prOgnant womOn in thO POoplO＇s Hospital of Yuhuan wOrO sOlOctOd, who accOptOd thyroid function scrOOning during prOgnancy. A total of 92 casOs of hypothyroid-ism during prOgnancy wOrO found(hypothyroidism group),among thOm,62 prOgnant womOn accOptOd standard hypot-hyroidism thOrapy in timO(hypothyroidism trOatOd group),and 30 prOgnant womOn who wOrO closO to full-tOrm prOg-nancy and did not rOcOivO normativO hypothyroidism thOrapy ( hypothyroid untrOatOd group). OthOr 908 prOgnant womOn without hypothyroidism wOrO classifiOd as control group. ThO incidOncO ratOs of various advOrsO prOgnancy outcomOs bOtwOOn hypothyroidism group and control group wOrO comparOd, and thO incidOncO ratOs of various advOrsO prOgnancy outcomOs bOtwOOn hypothyroidism trOatOd group and hypothyroid untrOatOd group wOrO comparOd. Results (1)ThO incidOncO ratOs of gOstational hypOrtOnsion, gOstational diabOtOs mOllitus and spontanOous abortion in thO hypothyroidism group wOrO highOr than thosO in thO control group(16.30% vs. 2.75% , 14.13% vs. 3.08% , 13.04% vs. 2.97% ) (χ2 =39.947, 26.497, 22.602,P=0.000, 0.000, 0.000).(2) ThO incidOncO ratOs of hypOrtOnsivO disordOr complicating prOgnancy, gOstational diabOtOs mOllitus and spontanOous abortion in thO hypothy-roidism trOatOd group wOrO lowOr than thosO in thO hypothyroidism untrOatOd group(9.68% vs. 33.33% , 8.06% vs. 26.67% , 8.06% vs. 23.33% )(χ2 =5.692, 5.766, 4.156,P=0.000, 0.000, 0.000).Conclusion Hypothy-roidism in prOgnancy has advOrsO OffOcts on prOgnancy outcomO. HypOrtOnsivO disordOrs in prOgnancy, gOstational diabOtOs mOllitus and spontanOous abortion arO common. ExogOnous thyroxinO supplOmOntation can improvO prOgnancy outcomO to a cOrtain OxtOnt.

Exploration about the protection mechanism of 5-hydroxy-1-methylhydantoin on paraquat poisoning model / 中华危重病急救医学

Objective To investigate the effects of 5-hydroxy-1-methylhydantoin (HMH) on kidney injury induced by paraquat (PQ). Methods Fifteen SPF healthy Kunming mice were randomly divided into normal saline (NS) control group, PQ poisoning model group and HMH intervention group, with 5 mice in each group. PQ poisoning model was challenged by one-time gavage of 30 mg/kg PQ solution. The NS group received the same amount of NS by gavage. The HMH group was given 100 mg/kg of HMH immediately after the model was made and continued to be gavaged. Mice in each group were sacrificed 1 day after HMH gavage and heart blood and renal tissue were harvested for examination. The morphological changes of renal tissue were observed under light microscope by hematoxylin-eosin (HE) staining. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in renal tissue were detected according to the instructions of the kit. The expression of heme oxygenase-1 (HO-1) and interleukin-1β (IL-1β) in renal tissues were detected by Western Blot. The serum metabolites were detected by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS), the overall distribution of each sample was observed by principal component analysis (PCA), the accuracy of the model was evaluated by multidimensional analysis orthogonal partial least squares-discriminant analysis (OPLS-DA), and the difference metabolites were screened by variable importance in the projection (VIP) value > 1. Results Light microscopic observation showed that: glomerular structure in NS group was clear, there was no hyperemia and inflammatory cell infiltration in renal interstitium and blood vessels. In PQ group, some glomeruli atrophy and necrosis, capillary congestion in glomeruli, infiltration of inflammatory cells around glomeruli, swelling of renal tubular epithelial cells, slight stenosis of lumen, and occasional necrosis and exfoliation of epithelial cells occurred. The degree of kidney injury in HMH group was significantly less than that in PQ group. Compared with the NS group, the content of MDA in the PQ group was significantly increased (nmol/g: 6.70±0.84 vs. 2.70±0.43, P < 0.01) and the activity of SOD was significantly decreased (kU/L: 33.30±4.66 vs. 50.20±3.23, P < 0.05), the protein expression of HO-1 and IL-1β were significantly increased (HO-1/β-actin: 1.11±0.12 vs. 0.61±0.13, IL-1β/β-actin: 0.93±0.13 vs. 0.32±0.06, both P < 0.05). Compared with the PQ group, the content of MDA in the HMH group was significantly decreased (nmol/g: 5.10±0.93 vs. 6.70±0.84, P < 0.05) and the activity of SOD was significantly increased (kU/L:61.00±9.02 vs. 33.30±4.66, P < 0.05), the protein expression of HO-1 was significantly decreased (HO-1/β-actin:0.77±0.07 vs. 1.11±0.12, P < 0.05), however, there was no significant difference in the protein expression of IL-1β (IL-1β/β-actin: 0.87±0.13 vs. 0.93±0.13, P > 0.05). Metabolite detection results showed that: compared with NS group, the levels of creatinine, glycine, succinic acid, fumaric acid and citric acid were significantly increased in the PQ group (VIP value was 1.50, 1.58, 1.64, 1.74 and 1.95 respectively, all P < 0.05), while the levels of palmitic acid, α-tocopherol and 6-phosphogluconic acid were significantly decreased (VIP value was 1.10, 1.55 and 1.56 respectively, all P < 0.05). Compared with the PQ group, the levels of creatinine and citric acid were significantly decreased in the HMH group (VIP value was 1.50 and 1.86, both P < 0.05), while trans-4-hydroxy-proline, D-glyceric acid, 2, 6-fructose phosphate, 6-phosphate gluconic acid and aminomalonic acid were significantly increased (VIP value was 1.36, 1.55, 1.63, 1.68 and 1.76 respectively, all P < 0.05). Conclusions HMH protects kidney injury caused by PQ poisoning by correcting tricarboxylic acids cycle disturbance, lipid peroxidation and energy metabolism disturbance, and its mechanism is related to the regulation of HO-1 protein expression through Nrf2 pathway.

Relationship of CSF and serum FGF-2 level with clinical parameters in motor neuron disease patients / 中华老年心脑血管病杂志

Objective To study the relationship of CSF and serum FGF-2 level with clinical parameters in MND patients.Methods Ninety-one MND patients served as a MND group and 40 noninflammtory nervous system disease patients served as a control group.Their CSF and serum FGF-2 level were measured by ELISA.The neurological deficit in ALS patients was assessed according to the modified ALSFRS-r,the progression of MND was assessed according to the DPR.The ALS patients were followed up,during which their survival time was recorded.Results The serum FGF-2 level was significantly higher in MND group than in control group (P＜0.01).The CSF,FGF-2 level were significantly higher in ALS patients of MND group than in those of control group (319.2±105.9 ng/L vs 241.7±34.3 ng/L,P＜0.01).The CSF and serum FGF-2 level were positively correlated with the duration of MND and negatively correlated with the DRP in ALS patients (P＜0.01).Survival analysis of MND patients indicated that the survival time of PMA patients was longer than that of PLS,ALS and PBP patients (P=0.000).The cumulative survival rate of ALS patients with a high serum FGF-2 level was significantly higher than that of those with a low serum FGF-2 level (P=0.002).Conclusion The CSF and serum FGF-2 level are higher in some MND patients and can be used as one of the biomarkers for evaluating the progression and predicting surrival.

Determination of Related Substances in Pantoprazole Sodium for Injection by HPLC / 中国药房

OBJECTIVE:To establish a method for the determination of related substances in Pantoprazole sodium for injec-tions. METHODS:HPLC method was adopted. The determination was performed on Kromasil Hypersil ODS column with mobile phases consisting of 0.01 mol/L potassium dihydrogen phosphate buffer solution(pH adjusted to 7.0)-acetonitrile(gradient elution) at a flow rate of 1.0 mL/min. The detection wavelength was set at 290 nm,and the column temperature was 40 ℃,and injection volume was 20 μL. RESULTS:The linear ranges of impurity A,impurity B,impurity C+E,and impurity D were 0.4168-1.0420μg/mL(r=0.9998),0.1950-0.4875 μg/mL(r=0.9999),0.3890-0.9725 μg/mL(r=0.9998),0.1986-0.4965 μg/mL(r=0.9998), respectively. The limits of quantitation were 0.834,0.780,1.556,0.794 ng/mL;the limits of detection were 0.417,0.390,0.778, 0.397 ng/mL,respectively. RSD of precision test was lower than 1.0%;in repetitive test,RSD for total peak area of impurity was lower than 1.0% ;the recoveries were 98.81% -102.49%(RSD=1.18% ,n=9),95.31% -98.44%(RSD=0.91% ,n=9), 96.88%-98.44%(RSD=0.52%,n=9)and 97.87%-101.28%(RSD=1.05%,n=9). CONCLUSIONS:The method is convenient, accurate and suitable for the determination of related substance in Pantoprazole sodium for injection.

Fast determination of aconitine in biological materials by LC-MS/MS / 中国法医学杂志

Objective To establish a HPLC-MS method for determination of aconitum alkaloids in biological samples. Methods The aconitum alkaloids were extracted from the whole blood by using acetonitrile-methanol (5:1 v/v) and then analyzed using HPLC-MS in multiple reaction monitoring (MRM) mode with positive ionization. The analytical column was Agilent Zorbax SB C18 (2.1mm×50mm, 1.8μm)and the mobile phase were water containing 0. 1 % formic acid : acetonitrile (60 : 40 v/v) in isocratic elution. Results The retention time of detection of the aconitine, hypaconitine and mesaconitine were 0.73 min, 0.77 min and 0.63 min, and the precursor product ion combinations of m/z 646.4 → 586.4, 616.1 → 556.5 and 632.4 → 572.1 were used for quantitative analysis, respectively. Calibration curve was linear within the range of 0.1-250 ng/mL with the LOD was 0.1ng/mL, and the coefficient of variation (CV) less than 5.42 % (n=6). The extraction recoveries of aconitine in blood were more than 90 %.Conclusion The results demonstrated that the present method was reliable and robust for natural drugs.

Impact analysis of public hospital corporate governance on their public welfare / 中华医院管理杂志

Objective To explore the influence of corporate governance at public hospitals on their nature of public welfare,in order to provide reference for promoting the reform of public hospital corporate governance.Methods Hypotheses of such impacts were raised by means of literature review. 460 questionnaires were collected from site survey,and four factors of public hospital corporate governance were used as independent variables,and five factors of the public welfare performance as dependent variables,for a correlation analysis and multiple linear regression analysis.Results A clear correlation is found among medical service level,and decision-making mechanism,the mechanism of key employees recruit/evaluation/incentive and their constraints (P < 0.05 ).Completion status of public health services is significantly correlated with the mechanism of recruit/evaluation/incentive and constraint,and their supervision mechanism as well(P <0.05).Medical technology level and cost of medical services are significantly correlated with decision-making mechanism.Conclusions In consideration of public hospital corporate governance,such mechanisms as decision-making,supervision,recruit,evaluation,incentive and constraint for key employees play a key role for public welfare performance.It is recommended to promote the hospital corporate governance reform from the above aspects.

Preventive effects of 5-hydroxy-1-methylhydantoin on paraquat-induced nephrotoxicity in rat / 中华危重病急救医学

ObjectiveTo investigate the protective effects of 5-hydroxy-1-methylhyantoin (HMH) on paraquat (PQ)-induced nephrotoxicity in rat and its possible mechanism.Methods Twenty-four male Sprague-Dawley (SD) rats were randomly divided into four groups: namely control, PQ, vitamin C and HMH groups, with 6 rats in each group. The rats in control group were given an injection of 2 mg/kg of normal saline intraperitoneally. The rats in PQ group were given an injection of 50 mg/kg of PQ intraperitoneally. The rats in vitamin C and HMH groups were given 1 mmol/kg of vitamin C or HMH through gastric tube right after PQ injection. The hydroxyl free radical scavenging ability of HMH and vitamin C was determined by Fenton method. Blood sample was collected after 24 hours of PQ treatment, then the animals were sacrificed and renal tissues were harvested. Blood urea nitrogen (BUN), serum creatinine (SCr), protein content of renal cortex, blood malondialdehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD) activity were determined.Results Both vitamin C and HMH showed a very good ability to scavenge hydroxyl radicals, and the 50% inhibiting concentration (IC50) was both 4.02 mg/mL. Compared with control group, serum BUN, SCr and MDA in renal tissue were significantly increased in PQ group, and the protein, GSH contents and SOD activity were significantly decreased [BUN (mmol/L): 40.80±2.49 vs. 13.67±1.58, SCr (μmol/L): 163.46±8.67 vs. 51.80±4.37, MDA (nmol/g): 7.51±0.23 vs. 4.52±0.33, protein (μmol/L): 0.94±0.14 vs. 1.35±0.10, GSH (mg/g): 1.08±0.48 vs. 3.30±0.44, SOD (kU/L): 70.74±6.42 vs. 112.89±8.72, allP 0.05).Conclusion HMH can protect the kidney against PQ-induced nephrotoxicity, and the mechanism of which maybe attributed to its anti-oxidation property and ability to scavenge hydroxyl radical.

Biomechanical principle of arcus plantaris and its clinical application / 中华创伤杂志(英文版)

OBJECTIVE: To analyze the principle mechanism of the arcus plantaris and its clinical application. METHODS: The states of forces sustained by the arcus plantaris were analyzed and calculated according to the mechanism of the quadratic parabolic arch. RESULTS: The aponeurosis plantaris corresponded to the pull rod of the arcus plantaris. The medial and lateral longitudinal arches formed by the pedal bones were stable with the rod, but unstable without the rod. In the latter condition, on loading, the force sustained by the parabolic arch became a force sustained by a simple beam, and the arcus plantaris tended to disappear and to be flattened. Clinically, 240 feet with talipes equinus were treated with triple arthrodesis. In 34 out of the reexamined 156 feet, the aponeurosis plantaris was cut in addition to the triple arthrodesis and was immobilized with cast for 3 months. One or two years later, their arcus plantaris disappeared, pain developed when walking, and some of them walked with the midtarsal joint against the ground. Then, the triple arthrodesis and shortening of the aponeurosis plantaris were applied on 18 cases, and osteotomy of the calcaneus and reconstruction of the aponeurosis plantaris were made on 10 cases and satisfactory effects were obtained. CONCLUSIONS: In order to achieve satisfactory therapeutic effects of the triple arthrodesis, we should reestablish the arcus plantaris and accurately treat the aponeurosis plantaris for the balance of the surrounding muscle force.